Increased Thromboxane Biosynthesis in Essential Thrombocythemia

Abstract

SummaryIn order to investigate the in vivo thromboxane (TX) biosynthesis in essential thromboeythemia (ET), we measured the urinary exeretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p <0.001) in thrombocythemic patients (4,063 ± 3,408 pg/mg creatinine; mean ± SD) than in controls (504 ± 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 >2 SD above the control mean. Patients with platelet number <1,000 × 109/1 (n = 25) had significantly higher (p <0.05) 11 -dehydro-TXB2 excretion than patients with higher platelet count (4,765 ± 3,870 pg/mg creatinine, n = 25, versus 2,279 ± 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging >55 was significantly higher than in the younger group (4,784 ± 3,948 pg/mg creatinine, n = 24, versus 2,405 ± 1,885 pg/mg creatinine, n = 16, p <0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p <0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p <0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age >55 and platelet count <1,000 × 1099/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo;2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.

Platelet activation and inhibition in polycythemia vera and essential thrombocythemia

“…Enhanced platelet activation has been consistently demonstrated in PV and ET, by different groups and methods either in vivo 7,8 or ex vivo 9,10 suggesting a pathogenetic link between activated platelets and thrombotic complications. In particular, markedly enhanced urinary excretion of thromboxane (TX) A 2 metabolites characterizes untreated ET and PV patients.…”

“…In particular, markedly enhanced urinary excretion of thromboxane (TX) A 2 metabolites characterizes untreated ET and PV patients. 7,8 TX metabolite excretion is a validated index of in vivo platelet activation. 11 As shown in Figure 1, the urinary excretion rates of 11-dehydro-TXB 2 reported in untreated ET 7 and PV 8 patients are at least comparable to unstable angina 12 and higher than a variety of clinical settings at increased cardiovascular risk.…”

“…7,8 TX metabolite excretion is a validated index of in vivo platelet activation. 11 As shown in Figure 1, the urinary excretion rates of 11-dehydro-TXB 2 reported in untreated ET 7 and PV 8 patients are at least comparable to unstable angina 12 and higher than a variety of clinical settings at increased cardiovascular risk. [13][14][15][16][17][18][19] Moreover, a role for circulating immature platelets as contributors to cardiovascular events and/or poor antiplatelet drug response has been emerging in both ET 10 and non-MPN diseases.…”

Enhanced platelet adhesion in essential thrombocythemia after in vitro activation

“…Flow cytometric studies in whole blood show increased platelet surface expression of P-selectin, increased binding of thrombospondin to platelets and increased amounts of platelet-leukocyte aggregates in MPN patients compared to controls [22,23]. Urine from ET patients has been reported to contain increased amounts of TXA 2 -metabolites [24]. Compared to normal subjects, an increased amount of platelet aggregates has been observed in blood from ET patients, and there is also an increased spontaneous aggregation of ET-platelets in plasma [25].…”

Prevention of thrombosis in polycythemia vera and essential thrombocythemia

“…In fact, in this specific setting, aspirin has an efficacy on venous and cerebrovascular events not found in other clinical conditions, which may be related to the suggested role of thromboxane hyperproduction in the thrombophilic state of these patients. 25,26 The efficacy of aspirin in preventing venous thromboembolism is suggested both by data from the ECLAP study (Figure 1) and by the retrospective analysis by De Stefano et al The retrospective nature of the latter study and the limited number of events recorded in the ECLAP study are important limitations but undoubtedly the two findings point in the same direction. Future studies will have to explore this issue as well as that of the apparent limited efficacy of hydroxyurea in preventing venous thromboembolism reported in the PT1 trial…”